Functionally Distinct Pools of Calcineurin Contribute to Depotentiation-like Synaptic Changes in the Lateral Amygdala During Auditory Fear Extinction

Abstract

Until recently, auditory fear extinction was not thought to modify substrates involved in the storage of the original auditory fear memory. Evidence now suggests that extinction results in the reversal of the fear conditioning-induced potentiation of thalamic inputs to the lateral amygdala. However, little is known about the molecular mechanisms that support this depotentiation of synaptic strength. Here we present behavioral and molecular evidence in support of the contribution of two distinct pools of the protein phosphatase calcineurin to depotentiation-like changes in lateral amygdala AMPA receptor trafficking during auditory fear extinction. Calcineurin protein that exists prior to the onset of extinction training is required for the reduction in conditional fear responses during the extinction session, whereas calcineurin protein that is synthesized during the extinction session is involved in the long-term retention of extinction learning. Furthermore, the pre-existing pool of calcineurin mediates endocytosis of GluR2-containing AMPARs, whereas the newly translated pool of calcineurin mediates reductions in AMPAR-stabilizing protein PSD-95. These results suggest that extinction involves the concerted actions of pre-existing and newly translated calcineurin to induce and stabilize AMPA receptor-mediated reductions in synaptic strength in the lateral amygdala.